The proposed research concerns the development of methods for the chemical synthesis of stereochemically complex medium- and large-ring carbocyclic compounds, and the application of these methods to the total synthesis of anti-neoplastic and biologically important macrocyclic natural products. In spite of the importance of these compounds, little progress has been made toward their synthesis for two reasons: difficulties are encountered in forming large, polyfunctionalized rings with intermolecular condensation of the acyclic precursors, and no general transformations are available for the construction of complex, flexible carbon chains of defined stereochemistry. A procedure for the formation of large-ring molecules by the cyclization of long chain precursors bound to an insoluble polymer will be investigated as an alternative to high dilution conditions for the reduction of competing intermolecular coupling. The application of this technique to the syntheses of the anti-tumor compound brefeldin A and anti-mitotic cytochalasins A, B, and F using a polymeric Wittig reagent, and to the synthesis of the antibiotic nonactin using a polymeric leaving group is outlined. Several methods for the stereoselective elaboration of acyclic carbon chains will be studied, and applied toward the syntheses of the anti-tumor rifamicins, the anti-leukemic Maytenus macrolides, and the aglycone of the erythromycin antibiotics. These methods include a sequence for the stereo-specific homologation of substituted homoallylic alcohols, stereocontrolled additions to Beta-hydroxycarbonyl chelates and conjugate displacement reactions of substituted cyclopropyloxiranes.